Yan Shuang, Song Man, Ping Jie, Lai Shu-Ting, Cao Xiao-Yu, Bai Chen-Jun, Xie Da-Fei, Guan Hua, Gao Shan-Shan, Zhou Ping-Kun
Institute for Environmental Medicine and Radiation Hygiene, School of Public Health, University of South China, Hengyang, Hunan Province, People's Republic of China.
Department of Radiation Biology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
Cell Death Discov. 2021 Sep 22;7(1):260. doi: 10.1038/s41420-021-00633-7.
To maintain genomic stability, the mammalian cells has evolved a coordinated response to DNA damage, including activation of DNA repair and cell cycle checkpoint processes. Exonuclease 1 (EXO1)-dependent excision of DNA ends is important for the initiation of homologous recombination (HR) repair of DNA breaks, which is thought to play a key role in activating the ATR-CHK1 pathway to induce G2/M cell cycle arrest. But the mechanism is still not fully understood. Here, we report that ZGRF1 forms complexes with EXO1 as well as other repair proteins and promotes DNA repair through HR. ZGRF1 is recruited to DNA damage sites in a MDC1-RNF8-BRCA1 dependent manner. Furthermore, ZGRF1 is important for the recruitment of RPA2 to DNA damage sites and the following ATR-CHK1 mediated G2/M checkpoint in response to irradiation. ZGRF1 null cells show increased sensitivity to many DNA-damaging agents, especially PARPi and irradiation. Collectively,our findings identify ZGRF1 as a novel regulator of DNA end resection and G2/M checkpoint. ZGRF1 is a potential target of radiation and PARPi cancer therapy.
为维持基因组稳定性，哺乳动物细胞已进化出对DNA损伤的协调反应，包括激活DNA修复和细胞周期检查点过程。核酸外切酶1（EXO1）依赖的DNA末端切除对于DNA断裂的同源重组（HR）修复的起始很重要，HR修复被认为在激活ATR-CHK1途径以诱导G2/M细胞周期停滞中起关键作用。但其机制仍未完全阐明。在此，我们报道ZGRF1与EXO1以及其他修复蛋白形成复合物，并通过HR促进DNA修复。ZGRF1以MDC1-RNF8-BRCA1依赖的方式被招募到DNA损伤位点。此外，ZGRF1对于RPA2被招募到DNA损伤位点以及随后ATR-CHK1介导的G2/M检查点以响应辐射很重要。ZGRF1缺失的细胞对许多DNA损伤剂，尤其是PARPi和辐射表现出更高的敏感性。总体而言，我们的研究结果确定ZGRF1是DNA末端切除和G2/M检查点的新型调节因子。ZGRF1是放射治疗和PARPi癌症治疗的潜在靶点。
